To investigate the events leading to the depletion of CD4 + T lymphocytes during long-term infection of human immunodeficiency virus type 1 (HIV-1), we infected human CD34 + cells-transplanted NOD/SCID/IL-2Rγ null mice with CXCR4-tropic and CCR5-tropic HIV-1. CXCR4-tropic HIV-1-infected mice were quickly depleted of CD4 + thymocytes and both CD45RA + naïve and CD45RA − memory CD4 + T lymphocytes, while CCR5-tropic HIV-1-infected mice were preferentially depleted of CD45RA − memory CD4 + T lymphocytes. Staining of HIV-1 p24 antigen revealed that CCR5-tropic HIV-1 preferentially infected effector memory T lymphocytes (T EM ) rather than central memory T lymphocytes. In addition, the majority of p24 + cells in CCR5-tropic HIV-1-infected mice were activated and in cycling phase. Taken together, our findings indicate that productive infection mainly takes place in the activated T EM in cycling phase and further suggest that the predominant infection in T EM would lead to the depletion of memory CD4 + T lymphocytes in CCR5-tropic HIV-1-infected mice.